Syndromic X-linked intellectual disability segregating with a missense variant in RLIM
Syndromic X-linked intellectual disability segregating with a missense variant in RLIM
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DOI：
10.1038/ejhg.2015.30
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发表时间：
2015-12-01
影响因子：
5.2
通讯作者：
Fiskerstrand, Torunn
中科院分区：
文献类型：
--
作者：
Tonne, Elin;Holdhus, Rita;Fiskerstrand, Torunn
我们描述了一个三代挪威家庭，他们患有一种新型 X 连锁智力障碍 (XLID) 综合征，其特征是轻微的面部畸形、自闭症和严重的喂养问题。通过外显子组测序，我们在两个受影响的男性远房表兄弟姐妹的 RLIM 基因中检测到了罕见的错义变异（c.1067A4G，p.(Tyr356Cys)）。桑格测序证实了四名受影响的男性（他们都不是兄弟姐妹）和三名可供检测的母亲中存在这种变异。该变体在 100 个挪威正常对照中不存在，也没有在变体数据库中报告过，并且根据计算机预测工具，该变体是有害的。临床表型和变异体共分离，与包含 242 个基因的共享区域 (36.09 Mb) 连锁，LOD 评分为 3.0。在这两个受影响的外显子组测序个体中，没有检测到 X 染色体上其他共享的罕见变异，并且所有女性携带者都具有极其扭曲的 X 染色体失活模式。 RLIM 编码 RING 锌指蛋白 12 (RNF12)，这是一种泛素连接酶，对于小鼠 X 失活至关重要，并且充当一系列转录因子的共同调节因子，特别是那些含有 LIM 同源域的转录因子。 RNF12 中 356 位的酪氨酸位于结合此类转录因子所必需的高度保守的结构域内。 RNF12 的表达在胚胎发生过程中广泛存在，并且在大脑皮层的外层中表达尤其高。需要进行功能研究来证明变异与表型之间明确的因果关系。随后的报告可能会证实 RLIM 变异在 XLID 患者中的作用。
We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A4G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.